ABSTRACT
Hereditary spastic paraplegia type 5 (SPG5) is an autosomal recessively inherited movement disorder characterized by progressive spastic gait disturbance and afferent ataxia. SPG5 is caused by bi-allelic loss of function mutations in CYP7B1 resulting in accumulation of the oxysterols 25-hydroxycholesterol and 27-hydroxycholesterol in serum and cerebrospinal fluid of SPG5 patients. An effect of 27- hydroxycholesterol via the estrogen and liver X receptors was previously shown on bone homeostasis. This study analyzed bone homeostasis and osteopenia in 14 SPG5 patients as a non-motor feature leading to a potential increased risk for bone fractures. T-Scores in CT bone density measurements were reduced, indicating osteopenia in SPG5 patients. Further, we analyzed various metabolites of bone homeostasis by ELISA in serum samples of these patients. We identified a lack of vitamin D3 metabolites (Calcidiol and Calcitriol), an increase in Sclerostin as a bone formation/mineralization inhibiting factor, and a decrease in cross-linked N-telopeptide of type I collagen (NTX), a marker indicating reduced bone resorption. As statin treatment has been found to lower oxysterol levels, we evaluated its effect in samples of the STOP-SPG5 trial and found atorvastatin to normalize the increased sclerostin levels. In summary, our study identified osteopenia as a non-motor feature in SPG5 and suggests the need for vitamin D3 substitution in SPG5 patients. Sclerostin may be considered a therapeutic target and biomarker in upcoming therapeutical trials in SPG5.
Subject(s)
Oxysterols , Spastic Paraplegia, Hereditary , Humans , Mutation , Spastic Paraplegia, Hereditary/genetics , Spastic Paraplegia, Hereditary/metabolism , Paraplegia , Homeostasis , Vitamin D/therapeutic useABSTRACT
Background: Despite a UK 5-year breast cancer survival rate of 86.6%, patients may develop breast cancer recurrence within the same breast after breast conserving surgery, as well as in the remaining skin or chest wall after mastectomy or in the ipsilateral lymph glands. These recurrences, collectively termed locoregional recurrence (LRR), occur in around 8% of patients within 10 years of their original diagnosis. Currently, there is a lack of robust information on the presentation and prevalence of LRR with no UK-specific clinical guidelines available for the optimal management of this patient group. Additionally, there is a need to identify patterns of LRR presentation and their progression, which will enable prognostic factors to be determined. This will subsequently enable the tailoring of treatment and improve patient outcome. Methods: The MARECA study is a prospective, multicentre cohort study recruiting patients diagnosed with breast cancer LRR +/- associated distant metastases. Over 50 UK breast units are participating in the study with the aim of recruiting at least 500 patients over a recruitment period of 24 months. The data collected will detail the tumour pathology, imaging results, surgical treatment, radiotherapy and systemic therapy of the primary and recurrent breast cancer. Study follow-up will be for up to 5 years following LRR diagnosis to determine subsequent oncological outcomes and evaluate potential prognostic factors. Discussion: This study will address the current knowledge gap and identify subgroups of patients who have less successful treatment outcomes. The results will determine the current management of LRR and the prognosis of patients diagnosed with breast cancer LRR +/- distant metastases in the UK, with the aim of establishing best practice and informing future national guidelines. The results will direct future research and inform the design of additional interventional trials and translational studies.
ABSTRACT
Vertigo and dizziness comprise a multisensory and multidisciplinary syndrome of different etiologies. The term "cerebellar vertigo and dizziness" comprises a heterogenous group of disorders with clinical signs of cerebellar dysfunction and is caused by vestibulo-cerebellar, vestibulo-spinal or cerebellar systems. About 10 % of patients in an outpatient clinic for vertigo and balance disorders suffer from cerebellar vertigo and dizziness. According to the course of the symptoms, one can considers 3 types: permanent complaints, recurrent episodes of vertigo and balance disorders, or an acute onset of complaints. The most common diagnoses in patients with cerebellar vertigo and dizziness were as follows: degenerative disease, hereditary forms and acquired forms. In a subgroup of patients with cerebellar vertigo, central cerebellar oculomotor dysfunction is indeed the only clinical correlate of the described symptoms. 81 % of patients with cerebellar vertigo suffer from permanent, persistent vertigo and dizziness, 31 % from vertigo attacks, and 21 % from both. Typical clinical cerebellar signs, including gait and limb ataxia or dysarthria, were found less frequently. Key to diagnosis is a focused history as well as a thorough clinical examination with particular attention to oculomotor function. Regarding oculomotor examination, the most common findings were saccadic smooth pursuit, gaze-evoked nystagmus, provocation nystagmus, rebound nystagmus, central fixation nystagmus, most commonly downbeat nystagmus, and disturbances of saccades. Thus, oculomotor examination is very sensitive in diagnosing cerebellar vertigo and dizziness, but not specific in distinguishing different etiologies. Laboratory examinations using posturography and a standardized gait analysis can support the diagnosis, but also help to estimate the risk of falls and to quantify the course and possible symptomatic treatment effects. Patients with cerebellar vertigo and dizziness should receive multimodal treatment.
ABSTRACT
BACKGROUND: This study was designed to identify common genetic susceptibility and shared genetic variants associated with acute radiation-induced toxicity across 4 cancer types (prostate, head and neck, breast, and lung). METHODS: A genome-wide association study meta-analysis was performed using 19 cohorts totaling 12â042 patients. Acute standardized total average toxicity (STATacute) was modelled using a generalized linear regression model for additive effect of genetic variants, adjusted for demographic and clinical covariates (rSTATacute). Linkage disequilibrium score regression estimated shared single-nucleotide variation (SNV-formerly SNP)-based heritability of rSTATacute in all patients and for each cancer type. RESULTS: Shared SNV-based heritability of STATacute among all cancer types was estimated at 10% (SE = 0.02) and was higher for prostate (17%, SE = 0.07), head and neck (27%, SE = 0.09), and breast (16%, SE = 0.09) cancers. We identified 130 suggestive associated SNVs with rSTATacute (5.0 × 10â8 < P < 1.0 × 10â5) across 25 genomic regions. rs142667902 showed the strongest association (effect allele A; effect size â0.17; P = 1.7 × 10â7), which is located near DPPA4, encoding a protein involved in pluripotency in stem cells, which are essential for repair of radiation-induced tissue injury. Gene-set enrichment analysis identified 'RNA splicing via endonucleolytic cleavage and ligation' (P = 5.1 × 10â6, P = .079 corrected) as the top gene set associated with rSTATacute among all patients. In silico gene expression analysis showed that the genes associated with rSTATacute were statistically significantly up-regulated in skin (not sun exposed P = .004 corrected; sun exposed P = .026 corrected). CONCLUSIONS: There is shared SNV-based heritability for acute radiation-induced toxicity across and within individual cancer sites. Future meta-genome-wide association studies among large radiation therapy patient cohorts are worthwhile to identify the common causal variants for acute radiotoxicity across cancer types.
Subject(s)
Genome-Wide Association Study , Neoplasms , Male , Humans , Neoplasms/genetics , Neoplasms/radiotherapy , Breast , Genetic Predisposition to DiseaseABSTRACT
BACKGROUND: Normal tissue complication probability (NTCP) models can be useful to estimate the risk of fibrosis after breast-conserving surgery (BCS) and radiotherapy (RT) to the breast. However, they are subject to uncertainties. We present the impact of contouring variation on the prediction of fibrosis. MATERIALS AND METHODS: 280 breast cancer patients treated BCS-RT were included. Nine Clinical Target Volume (CTV) contours were created for each patient: i) CTV_crop (reference), cropped 5 mm from the skin and ii) CTV_skin, uncropped and including the skin, iii) segmenting the 95% isodose (Iso95%) and iv) 3 different auto-contouring atlases generating uncropped and cropped contours (Atlas_skin/Atlas_crop). To illustrate the impact of contour variation on NTCP estimates, we applied two equations predicting fibrosis grade ≥ 2 at 5 years, based on Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) models, respectively, to each contour. Differences were evaluated using repeated-measures ANOVA. For completeness, the association between observed fibrosis events and NTCP estimates was also evaluated using logistic regression. RESULTS: There were minimal differences between contours when the same contouring approach was followed (cropped and uncropped). CTV_skin and Atlas_skin contours had lower NTCP estimates (-3.92%, IQR 4.00, p < 0.05) compared to CTV_crop. No significant difference was observed for Atlas_crop and Iso95% contours compared to CTV_crop. For the whole cohort, NTCP estimates varied between 5.3% and 49.5% (LKB) or 2.2% and 49.6% (RS) depending on the choice of contours. NTCP estimates for individual patients varied by up to a factor of 4. Estimates from "skin" contours showed higher agreement with observed events. CONCLUSION: Contour variations can lead to significantly different NTCP estimates for breast fibrosis, highlighting the importance of standardising breast contours before developing and/or applying NTCP models.
Subject(s)
Breast Neoplasms , Fibrocystic Breast Disease , Female , Humans , Radiotherapy Dosage , Breast Neoplasms/radiotherapy , Breast Neoplasms/surgery , Breast/diagnostic imaging , Radiotherapy Planning, Computer-Assisted , Probability , FibrosisABSTRACT
BACKGROUND: Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma. METHODS: An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment. DISCUSSION: The results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort. TRIAL REGISTRATION: NCT05479032.
Subject(s)
Brain Injuries, Traumatic , Brain Injuries , Ischemic Stroke , Adult , Humans , Amantadine/therapeutic use , Clinical Trials, Phase II as Topic , Coma , Pilot Projects , Prospective Studies , Proof of Concept StudyABSTRACT
BACKGROUND AND PURPOSE: Up to a quarter of breast cancer patients treated by surgery and radiotherapy experience clinically significant toxicity. If patients at high risk of adverse effects could be identified at diagnosis, their treatment could be tailored accordingly. This study was designed to identify common single nucleotide polymorphisms (SNPs) associated with toxicity two years following whole breast radiotherapy. MATERIALS AND METHODS: A genome-wide association study (GWAS) was performed in 1,640 breast cancer patients with complete SNP, clinical, treatment and toxicity data, recruited across 18 European and US centres into the prospective REQUITE cohort study. Toxicity data (CTCAE v4.0) were collected at baseline, end of radiotherapy, and annual follow-up. A total of 7,097,340 SNPs were tested for association with the residuals of toxicity endpoints, adjusted for clinical, treatment co-variates and population substructure. RESULTS: Quantile-quantile plots showed more associations with toxicity above the p < 5 × 10-5 level than expected by chance. Eight SNPs reached genome-wide significance. Nipple retraction grade ≥ 2 was associated with the rs188287402 variant (p = 2.80 × 10-8), breast oedema grade ≥ 2 with rs12657177 (p = 1.12 × 10-10), rs75912034 (p = 1.12 × 10-10), rs145328458 (p = 1.06 × 10-9) and rs61966612 (p = 1.23 × 10-9), induration grade ≥ 2 with rs77311050 (p = 2.54 × 10-8) and rs34063419 (p = 1.21 × 10-8), and arm lymphoedema grade ≥ 1 with rs643644 (p = 3.54 × 10-8). Heritability estimates across significant endpoints ranged from 25% to 39%. Our study did not replicate previously reported SNPs associated with breast radiation toxicity at the pre-specified significance level. CONCLUSIONS: This GWAS for long-term breast radiation toxicity provides further evidence for significant association of common SNPs with distinct toxicity endpoints.
Subject(s)
Breast Neoplasms , Radiation Injuries , Humans , Female , Breast Neoplasms/genetics , Breast Neoplasms/radiotherapy , Genome-Wide Association Study , Cohort Studies , Prospective Studies , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: In Hereditary Spastic Paraplegia (HSP) type 4 (SPG4) a length-dependent axonal degeneration in the cortico-spinal tract leads to progressing symptoms of hyperreflexia, muscle weakness, and spasticity of lower extremities. Even before the manifestation of spastic gait, in the prodromal phase, axonal degeneration leads to subtle gait changes. These gait changes - depicted by digital gait recording - are related to disease severity in prodromal and early-to-moderate manifest SPG4 participants. METHODS: We hypothesize that dysfunctional neuro-muscular mechanisms such as hyperreflexia and muscle weakness explain these disease severity-related gait changes of prodromal and early-to-moderate manifest SPG4 participants. We test our hypothesis in computer simulation with a neuro-muscular model of human walking. We introduce neuro-muscular dysfunction by gradually increasing sensory-motor reflex sensitivity based on increased velocity feedback and gradually increasing muscle weakness by reducing maximum isometric force. RESULTS: By increasing hyperreflexia of plantarflexor and dorsiflexor muscles, we found gradual muscular and kinematic changes in neuro-musculoskeletal simulations that are comparable to subtle gait changes found in prodromal SPG4 participants. CONCLUSIONS: Predicting kinematic changes of prodromal and early-to-moderate manifest SPG4 participants by gradual alterations of sensory-motor reflex sensitivity allows us to link gait as a directly accessible performance marker to emerging neuro-muscular changes for early therapeutic interventions.
Subject(s)
Paraplegia , Reflex, Abnormal , Humans , Computer Simulation , Gait , Muscle Weakness , ParesisABSTRACT
Fatigue is common in breast-cancer survivors. Our study assessed fatigue longitudinally in breast cancer patients receiving adjuvant radiotherapy (RT) and aimed to identify risk factors associated with long-term fatigue and underlying fatigue trajectories. Fatigue was measured in a prospective multicenter cohort (REQUITE) using the Multidimensional Fatigue Inventory (MFI-20) and analyzed using mixed models. Multivariable logistic models identified factors associated with fatigue dimensions at 2 years post-RT and latent class growth analysis identified individual fatigue trajectories. A total of 1443, 1302, 1203 and 1098 patients completed the MFI-20 at baseline, end of RT, after 1 and 2 years. Overall, levels of fatigue significantly increased from baseline to end of RT for all fatigue dimensions (P < .05) and returned to baseline levels after 2 years. A quarter of patients were assigned to latent trajectory high (23.7%) and moderate (24.8%) fatigue classes, while 46.3% and 5.2% to the low and decreasing fatigue classes, respectively. Factors associated with multiple fatigue dimensions at 2 years include age, BMI, global health status, insomnia, pain, dyspnea and depression. Fatigue present at baseline was consistently associated with all five MFI-20 fatigue dimensions (ORGeneralFatigue = 3.81, P < .001). From latent trajectory analysis, patients with a combination of factors such as pain, insomnia, depression, younger age and endocrine therapy had a particularly high risk of developing early and persistent high fatigue years after treatment. Our results confirmed the multidimensional nature of fatigue and will help clinicians identify breast cancer patients at higher risk of having persistent/late fatigue so that tailored interventions can be delivered.
Subject(s)
Breast Neoplasms , Sleep Initiation and Maintenance Disorders , Humans , Female , Breast Neoplasms/therapy , Prospective Studies , Sleep Initiation and Maintenance Disorders/complications , Risk Factors , Fatigue/etiology , Fatigue/complications , Pain , Quality of LifeABSTRACT
PURPOSE: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. METHODS: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb-July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. RESULTS: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32-81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7-8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months' treatment duration; median of 4 mm [IQR - 20, 4]. In a small subset of patients (n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (< 10%), with at least one month's duration of BrET. DISCUSSION: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials.
Subject(s)
Breast Neoplasms , COVID-19 , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Pandemics , Ki-67 Antigen/metabolism , Cohort Studies , Prognosis , Neoadjuvant TherapySubject(s)
Arteriovenous Fistula , Brain Edema , Central Nervous System Vascular Malformations , Humans , Brain Edema/diagnostic imaging , Brain Edema/etiology , Central Nervous System Vascular Malformations/complications , Central Nervous System Vascular Malformations/diagnostic imaging , Cerebral AngiographyABSTRACT
PURPOSE: A James Lind Alliance priority setting partnership was developed to identify research priorities in breast cancer surgery from individuals with lived experience, at high genetic risk of breast cancer, and healthcare professionals (HCPs). METHODS: 'Uncertainties' were collected using an online survey. Following an evidence check and development of summary questions, an interim survey asked participants to rank their top 10 research priorities from the question list. Top-ranked questions from patient/carer, high-risk and professional groups were carried forward for discussion to a final online prioritisation workshop. RESULTS: 260 participants (101 patients/carers, 156 HCPs) submitted 940 uncertainties via the initial survey. These were analysed thematically into 128 summary questions in six topic areas. Following evidence checking, 59 questions were included in the interim survey which was completed by 572 respondents. Marked differences were seen in questions prioritised by patients/carers, HCPs and women at high-risk. The top eight priorities in patient/carer and professional groups and top two priorities for high-risk women were carried forward to the online workshop at which 22 participants discussed and agreed the final top 10. Key themes included de-escalation of breast and axillary surgery, factors impacting the development/detection of locoregional recurrence and optimal provision of support for informed treatment decision-making. CONCLUSION: The top 10 research priorities in breast cancer surgery have been agreed. However, the observed differences in research priorities identified by patients and professional groups were not anticipated. Top priorities from both groups should inform future UK breast cancer surgical research, to ensure that it addresses questions that are important to breast cancer community as a whole.
Subject(s)
Biomedical Research , Breast Neoplasms , Humans , Female , Breast Neoplasms/surgery , Health Priorities , Neoplasm Recurrence, Local , Surveys and Questionnaires , United KingdomABSTRACT
This cohort study aimed to characterize the prodromal phase of hereditary spastic paraplegia type 4 (SPG4) using biomarkers and clinical signs and symptoms that develop before manifest gait abnormalities. Fifty-six first-degree relatives at risk of developing SPG4 underwent blinded genotyping and standardized phenotyping, including the Spastic Paraplegia Rating Scale (SPRS), complicating symptoms, non-motor affection, Three-Minute Walk, and neurophysiological assessment. Automated MR image analysis was used to compare volumetric properties. CSF of 33 probands was analysed for neurofilament light chain (NfL), tau, and amyloid-ß (Aß). Thirty participants turned out to be SPAST mutation carriers, whereas 26 did not inherit a SPAST mutation. Increased reflexes, ankle clonus, and hip abduction weakness were more frequent in prodromal mutation carriers but were also observed in non-mutation carriers. Only Babinski's sign differentiated reliably between the two groups. Timed walk and non-motor symptoms did not differ between groups. Whereas most mutation carriers had total SPRS scores of 2 points or more, only two non-mutation carriers reached more than 1 point. Motor evoked potentials revealed no differences between mutation and non-mutation carriers. We found NfL but not tau or Aß to rise in CSF of mutation carriers when approaching the time point of predicted disease manifestation. Serum NfL did not differ between groups. Volumetric MRI analyses did not reveal group differences apart from a smaller cingulate gyrus in mutation carriers. This study depicts subtle clinical signs which develop before gait abnormalities in SPG4. Long-term follow-up is needed to study the evolution of SPG4 in the prodromal stage and conversion into manifest disease. NfL in CSF is a promising fluid biomarker that may indicate disease activity in prodromal SPG4 but needs further evaluation in longitudinal studies.
Subject(s)
Spastic Paraplegia, Hereditary , Humans , Spastic Paraplegia, Hereditary/genetics , Cohort Studies , Paraplegia/genetics , Mutation/genetics , Amyloid beta-Peptides/genetics , Spastin/geneticsABSTRACT
Usage of MR imaging biomarkers is limited to experts. Automatic quantitative reports provide access for clinicians to data analysis. Automated data analysis was tested for usability in a small cohort of patients with hereditary spastic paraplegia type 4 (SPG4). We analyzed 3T MRI 3D-T1 datasets of n = 25 SPG4 patients and matched healthy controls using a commercial segmentation tool (AIRAscore structure 2.0.1) and standard VBM. In SPG4 total brain volume was reduced by 27.6 percentiles (p = 0.001) caused mainly by white matter loss (- 30.8th, p < 0.001) and stable total gray matter compared to controls. Brain volume loss occurred in: midbrain (- 41.5th, p = 0.001), pons (- 36.5th, p = 0.02), hippocampus (- 20.9th, p = 0.002), and gray matter of the cingulate gyrus (- 17.0th, p = 0.02). Ventricular volumes increased as indirect measures of atrophy. Group comparisons using percentiles aligned with results from VBM analyses. Quantitative imaging reports proved to work as an easily accessible, fully automatic screening tool for clinicians, even in a small cohort of a rare genetic disorder. We could delineate the involvement of white matter and specify involved brain regions. Group comparisons using percentiles provide comparable results to VBM analysis and are, therefore, a suitable and simple screening tool for all clinicians with and without in-depth knowledge of image processing.
Subject(s)
Spastic Paraplegia, Hereditary , Humans , Spastic Paraplegia, Hereditary/genetics , Rare Diseases , Paraplegia , Brain/diagnostic imaging , Magnetic Resonance Imaging/methodsABSTRACT
Introduction: We hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). Methods: The study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in ≥2 (WS2) or ≥3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. Results: In REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L·Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L·Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58. Conclusion: Increasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT.
ABSTRACT
Spinal diffusion tensor imaging (sDTI) is still a challenging technique for selectively evaluating anatomical areas like the pyramidal tracts (PT), dorsal columns (DC), and anterior horns (AH) in clinical routine and for reliably quantifying white matter anisotropy and diffusivity. In neurodegenerative diseases, the value of sDTI is promising but not yet well understood. The objective of this prospective, single-center study was to evaluate the long fiber tract degeneration within the spinal cord in normal aging (nâ¯=â¯125) and to prove its applicability in pathologic conditions as in patients with molecular genetically confirmed hereditary spastic paraplegias (HSP; nâ¯=â¯40), a prototypical disease of the first motor neuron and in some genetic variants with affection of the dorsal columns. An optimized monopolar Stejskal-Tanner sequence for high-resolution, axial sDTI of the cervical spinal cord at 3.0â¯T with advanced standardized evaluation methods was developed for a robust DTI value estimation of PT, DC, and AH in both groups. After sDTI measurement at C2, an automatic motion correction and an advanced semi-automatic ROI-based, standardized evaluation of white matter anisotropy and diffusivity was performed to obtain regional diffusivity measures for PT, DC, and AH. Reliable and stable sDTI values were acquired in a healthy population without significant decline between age 20 and 65. Reference values for PT, DC, and AH for fractional anisotropy (FA), mean diffusivity (MD), and radial diffusivity (RD) were established. In HSP patients, the decline of the long spinal fiber tracts could be demonstrated by diffusivity abnormalities in the pyramidal tracts with significantly reduced PTFA (pâ¯<â¯0.001), elevated PTRD (pâ¯=â¯0.002) and reduced PTMD (pâ¯=â¯0.003) compared to healthy controls. Furthermore, FA was significantly reduced in DCFA (pâ¯<â¯0.001) with no differences in AH. In a genetically homogeneous subgroup of SPG4 patients (nâ¯=â¯12) with affection of the dorsal columns, DCRD significantly correlated with the overall disease severity as measured by the Spastic Paraplegia Rating Scale (SPRS) (r = - 0.713, pâ¯=â¯0.009). With the most extensive sDTI study in vivo to date, we showed that axial sDTI combined with motion correction and advanced data post-processing strategies enables robust measurements and is ready to use, allowing recognition and quantification of disease- and age-related changes of the PT, DC, and AH. These results may also encourage the usage of sDTI in other neurodegenerative diseases with spinal cord involvement to explore its capability as selective biomarkers.
Subject(s)
Diffusion Tensor Imaging , White Matter , Animals , Humans , Young Adult , Adult , Middle Aged , Aged , Diffusion Tensor Imaging/methods , Prospective Studies , White Matter/diagnostic imaging , White Matter/pathology , Anisotropy , Pyramidal Tracts/diagnostic imagingABSTRACT
BACKGROUND: Circadian rhythm impacts broad biological processes, including response to cancer treatment. Evidence conflicts on whether treatment time affects risk of radiotherapy side-effects, likely because of differing time analyses and target tissues. We previously showed interactive effects of time and genotypes of circadian genes on late toxicity after breast radiotherapy and aimed to validate those results in a multi-centre cohort. METHODS: Clinical and genotype data from 1690 REQUITE breast cancer patients were used with erythema (acute; n=340) and breast atrophy (two years post-radiotherapy; n=514) as primary endpoints. Local datetimes per fraction were converted into solar times as predictors. Genetic chronotype markers were included in logistic regressions to identify primary endpoint predictors. FINDINGS: Significant predictors for erythema included BMI, radiation dose and PER3 genotype (OR 1.27(95%CI 1.03-1.56); P < 0.03). Effect of treatment time effect on acute toxicity was inconclusive, with no interaction between time and genotype. For late toxicity (breast atrophy), predictors included BMI, radiation dose, surgery type, treatment time and SNPs in CLOCK (OR 0.62 (95%CI 0.4-0.9); P < 0.01), PER3 (OR 0.65 (95%CI 0.44-0.97); P < 0.04) and RASD1 (OR 0.56 (95%CI 0.35-0.89); P < 0.02). There was a statistically significant interaction between time and genotypes of circadian rhythm genes (CLOCK OR 1.13 (95%CI 1.03-1.23), P < 0.01; PER3 OR 1.1 (95%CI 1.01-1.2), P < 0.04; RASD1 OR 1.15 (95%CI 1.04-1.28), P < 0.008), with peak time for toxicity determined by genotype. INTERPRETATION: Late atrophy can be mitigated by selecting optimal treatment time according to circadian genotypes (e.g. treat PER3 rs2087947C/C genotypes in mornings; T/T in afternoons). We predict triple-homozygous patients (14%) reduce chance of atrophy from 70% to 33% by treating in mornings as opposed to mid-afternoon. Future clinical trials could stratify patients treated at optimal times compared to those scheduled normally. FUNDING: EU-FP7.
Subject(s)
Period Circadian Proteins , Radiation Injuries , Atrophy , Circadian Rhythm/genetics , Genotype , Humans , Period Circadian Proteins/genetics , Prospective Studies , ras Proteins/geneticsABSTRACT
BACKGROUND: In hereditary spastic paraplegia type 4 (SPG4), subclinical gait changes might occur years before patients realize gait disturbances. The prodromal phase of neurodegenerative disease is of particular interest to halt disease progression by future interventions before impairment has manifested. OBJECTIVE: The objective of this study was to identify specific movement abnormalities before the manifestation of gait impairment and quantify disease progression in the prodromal phase. METHODS: Seventy subjects participated in gait assessment, including 30 prodromal SPAST pathogenic variant carriers, 17 patients with mild-to-moderate manifest SPG4, and 23 healthy control subjects. An infrared-camera-based motion capture system assessed gait to analyze features such as range of motion and continuous angle trajectories. Those features were correlated with disease severity as assessed by the Spastic Paraplegia Rating Scale, neurofilament light chain as a fluid biomarker indicating neurodegeneration, and motor-evoked potentials. RESULTS: Compared with healthy control subjects, we found an altered gait pattern in prodromal pathogenic variant carriers during the swing phase in the segmental angle of the foot (Dunn's post hoc test, q = 3.1) and heel ground clearance (q = 2.8). Furthermore, range of motion of segmental angle was reduced for the foot (q = 3.3). These changes occurred in prodromal pathogenic variant carriers without quantified leg spasticity in clinical examination. Gait features correlated with neurofilament light chain levels, central motor conduction times of motor-evoked potentials, and Spastic Paraplegia Rating Scale score. CONCLUSIONS: Gait analysis can quantify changes in prodromal and mild-to-moderate manifest SPG4 patients. Thus, gait features constitute promising motor biomarkers characterizing the subclinical progression of spastic gait and might help to evaluate interventions in early disease stages. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.